Spasmodic dysphonia, or laryngeal dystonia, is a chronic debilitating condition that selectively affects speech production due to involuntary spasms in the laryngeal muscles. SD often extends beyond vocal communication impairment and causes significant occupational disability and life-long social isolation. SD becomes even more incapacitating when it is associated with dystonic voice tremor (VT), which is present in about 1/3 of SD patients and is characterized by the inability to sustain a vowel for more than a few seconds. Current treatment of these disorders is limited to the temporary management of voice symptoms with repeated injections of botulinum toxin into the laryngeal muscles, which, however, are not effective in all SD patients and even less so in combined SD/VT cases. There is, therefore, a critical need to identify alternative therapeutic options that are specifically targeting the pathophysiology of SD and VT. On the other hand, the design and use of such novel therapeutic approaches will be largely unattainable if their central mechanisms of action remain unknown. Our long-term goal is to determine the pathophysiology of SD and related disorders, such as VT, and develop new diagnostic and treatment options for these patients. The objective of this application is to elucidate the primary determinants of clinical response to a novel oral medication, sodium oxybate (Xyrem), in alcohol-responsive SD and SD/VT patients. Our central hypothesis is that clinical benefits of sodium oxybate are contingent upon selective modulation of neural alterations associated with genetics susceptibility factors that underlie symptom responsiveness to alcohol in SD and VT. Using a comprehensive approach of clinico- behavioral testing, neuroimaging and pharmacogenetics, our central hypothesis will be tested by pursuing two specific aims, which will: (1) determine the clinical response of SD and VT symptoms to sodium oxybate, and (2) identify primary markers of clinical benefits of sodium oxybate in these disorders. This research is innovative because it will use a controlled experimental design that focuses on detailed characterization of primary effects of a novel oral medication, sodium oxybate, for treatment of SD and VT symptoms. The proposed research is significant because it is expected to have broad translational impact on improving the clinical management of patients with SD and VT, opening new therapeutic horizons for treatment of these and similar disorders.